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Comparative Study
. 2015 Dec;47(12):1415-25.
doi: 10.1038/ng.3437. Epub 2015 Nov 9.

Genetic Fine Mapping and Genomic Annotation Defines Causal Mechanisms at Type 2 Diabetes Susceptibility Loci

Kyle J Gaulton  1   2 Teresa Ferreira  1 Yeji Lee  3 Anne Raimondo  4 Reedik Mägi  5 Michael E Reschen  6 Anubha Mahajan  1 Adam Locke  3 N William Rayner  1   4   7 Neil Robertson  1   4 Robert A Scott  8 Inga Prokopenko  9 Laura J Scott  3 Todd Green  10 Thomas Sparso  11 Dorothee Thuillier  12 Loic Yengo  12 Harald Grallert  13   14   15 Simone Wahl  13   14   15 Mattias Frånberg  16   17   18 Rona J Strawbridge  16 Hans Kestler  19   20 Himanshu Chheda  21 Lewin Eisele  22 Stefan Gustafsson  23 Valgerdur Steinthorsdottir  24 Gudmar Thorleifsson  24 Lu Qi  25   26   27   28 Lennart C Karssen  29 Elisabeth M van Leeuwen  29 Sara M Willems  8   29 Man Li  30 Han Chen  31   32 Christian Fuchsberger  3 Phoenix Kwan  3 Clement Ma  3 Michael Linderman  33 Yingchang Lu  34 Soren K Thomsen  4 Jana K Rundle  4 Nicola L Beer  1   4 Martijn van de Bunt  1   4 Anil Chalisey  6 Hyun Min Kang  3 Benjamin F Voight  35 Gonçalo R Abecasis  3 Peter Almgren  36 Damiano Baldassarre  37   38 Beverley Balkau  39   40 Rafn Benediktsson  41   42 Matthias Blüher  43   44 Heiner Boeing  45 Lori L Bonnycastle  46 Erwin P Bottinger  47 Noël P Burtt  10 Jason Carey  10 Guillaume Charpentier  48 Peter S Chines  46 Marilyn C Cornelis  49 David J Couper  50 Andrew T Crenshaw  10 Rob M van Dam  26   51 Alex S F Doney  52   53 Mozhgan Dorkhan  54 Sarah Edkins  7 Johan G Eriksson  55   56   57   58 Tonu Esko  5   59   60 Elodie Eury  61 João Fadista  36 Jason Flannick  10 Pierre Fontanillas  10 Caroline Fox  62   63 Paul W Franks  26   36   64   65 Karl Gertow  16 Christian Gieger  13   14 Bruna Gigante  66 Omri Gottesman  47 George B Grant  10 Niels Grarup  11 Christopher J Groves  4 Maija Hassinen  67 Christian T Have  11 Christian Herder  68   69 Oddgeir L Holmen  70 Astradur B Hreidarsson  42 Steve E Humphries  71 David J Hunter  25   26   27   72 Anne U Jackson  3 Anna Jonsson  36 Marit E Jørgensen  73 Torben Jørgensen  74   75   76 Wen-Hong L Kao  30 Nicola D Kerrison  8 Leena Kinnunen  55 Norman Klopp  13   77 Augustine Kong  24 Peter Kovacs  43   44 Peter Kraft  25   32   72 Jasmina Kravic  36 Cordelia Langford  7 Karin Leander  66 Liming Liang  25   32 Peter Lichtner  78 Cecilia M Lindgren  1   10 Eero Lindholm  36 Allan Linneberg  74   79   80 Ching-Ti Liu  31 Stéphane Lobbens  61 Jian'an Luan  8 Valeriya Lyssenko  36   73 Satu Männistö  55 Olga McLeod  16 Julia Meyer  81 Evelin Mihailov  5 Ghazala Mirza  82 Thomas W Mühleisen  83   84   85 Martina Müller-Nurasyid  81   86   87   88 Carmen Navarro  89   90   91 Markus M Nöthen  83   84 Nikolay N Oskolkov  36 Katharine R Owen  4   92 Domenico Palli  93 Sonali Pechlivanis  22 Leena Peltonen  7   10   21   55 John R B Perry  8 Carl G P Platou  70   94 Michael Roden  68   69   95 Douglas Ruderfer  96 Denis Rybin  97 Yvonne T van der Schouw  98 Bengt Sennblad  16   17 Gunnar Sigurðsson  42   99 Alena Stančáková  100 Gerald Steinbach  101 Petter Storm  36 Konstantin Strauch  81   87 Heather M Stringham  3 Qi Sun  26   27 Barbara Thorand  14   15 Emmi Tikkanen  21   102 Anke Tonjes  43   44 Joseph Trakalo  1 Elena Tremoli  37   38 Tiinamaija Tuomi  21   58   103   104 Roman Wennauer  105 Steven Wiltshire  1 Andrew R Wood  106 Eleftheria Zeggini  7 Ian Dunham  107 Ewan Birney  107 Lorenzo Pasquali  108   109   110 Jorge Ferrer  111   112 Ruth J F Loos  8   34   47   113 Josée Dupuis  31   62 Jose C Florez  60   114   115   116 Eric Boerwinkle  117   118 James S Pankow  119 Cornelia van Duijn  29   120 Eric Sijbrands  105 James B Meigs  114   121 Frank B Hu  25   26   27 Unnur Thorsteinsdottir  24   41 Kari Stefansson  24   41 Timo A Lakka  67   122   123 Rainer Rauramaa  67   123 Michael Stumvoll  43   44 Nancy L Pedersen  124 Lars Lind  125 Sirkka M Keinanen-Kiukaanniemi  126   127 Eeva Korpi-Hyövälti  128 Timo E Saaristo  129   130 Juha Saltevo  131 Johanna Kuusisto  100 Markku Laakso  100 Andres Metspalu  5   132 Raimund Erbel  133 Karl-Heinz Jöcke  122 Susanne Moebus  22 Samuli Ripatti  7   21   102   134 Veikko Salomaa  55 Erik Ingelsson  1   23 Bernhard O Boehm  135   136 Richard N Bergman  137 Francis S Collins  46 Karen L Mohlke  138 Heikki Koistinen  55   139   140 Jaakko Tuomilehto  55   141   142   143 Kristian Hveem  70 Inger Njølstad  144 Panagiotis Deloukas  7   145 Peter J Donnelly  1   146 Timothy M Frayling  106 Andrew T Hattersley  147 Ulf de Faire  66 Anders Hamsten  16 Thomas Illig  13   77 Annette Peters  14   15   88 Stephane Cauchi  12 Rob Sladek  148   149 Philippe Froguel  9   12   61 Torben Hansen  11   150 Oluf Pedersen  11 Andrew D Morris  151 Collin N A Palmer  52   53 Sekar Kathiresan  10   115   152 Olle Melander  36 Peter M Nilsson  36 Leif C Groop  21   36 Inês Barroso  7   153   154 Claudia Langenberg  8 Nicholas J Wareham  8 Christopher A O'Callaghan  6 Anna L Gloyn  1   4   92 David Altshuler  10   114   115   116   155   156 Michael Boehnke  3 Tanya M Teslovich  3 Mark I McCarthy  1   4   92 Andrew P Morris  1   5   157   158 DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium
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Free PMC article
Comparative Study

Genetic Fine Mapping and Genomic Annotation Defines Causal Mechanisms at Type 2 Diabetes Susceptibility Loci

Kyle J Gaulton et al. Nat Genet. .
Free PMC article

Abstract

We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.

Conflict of interest statement

COMPETING FINANCIAL INTERESTS

V.Steinthorsdottir, G.T., A.K., U.T., and K.Stefansson are employed by deCODE Genetics/Amgen inc. I.B. and spouse own stock in GlaxoSmithKline and Incyte.

Figures

Figure 1
Figure 1. FOX2A bound sites are a genomic marker of T2D risk variants
(A) Variants in ChIP-seq binding sites for 165 proteins were tested for enrichment of posterior probabilities compared to variants in shifted sites. Variants in FOXA2 ChIP-seq sites were significantly enriched (p<0.00030). (B) FOXA2 ChIP-seq sites were partitioned based on overlap with other genomic features. There was stronger enrichment in: (i) FOXA2 sites overlapping a ChIP-seq site for another protein compared to unique sites; (ii) sites identified in primary islets compared to HepG2 or primary liver cells; and (iii) sites overlapping islet enhancers compared to those that did not (**p<0.00030; *p<0.05). (C) Variants at each signal were tested for FOXA2 enrichment. Nineteen signals had greater enrichment than expected compared to shifted sites; at 15 signals this enrichment was nominally-significant (p<0.05). (D) FOXA2-bound variants disrupting recognition motifs have an increased probability of being causal.
Figure 2
Figure 2. The lone variant in the 99% credible set at the MTNR1B locus affects FOXA2-bound enhancer activity
(A) The intronic variant, rs10830963, has 99.8% probability of driving the association signal at the MTRN1B locus. This variant overlaps a FOXA2 binding site, and the risk allele G is predicted to create a de novo recognition motif, which closely matches the NEUROD1 consensus. (B) Electrophoretic mobility shift assay of a 25bp fragment surrounding both alleles in EndoC-βH1 cell extracts. Proteins were bound to both alleles. In the presence of a NEUROD1 antibody, only the risk allele band was super-shifted, and in the presence of an unlabelled NEUROD1 consensus probe, the signal was competed away. NE: nuclear extract. (C, D) The 224bp sequence surrounding each allele was cloned into a luciferase reporter construct containing a minimal promoter and tested for luciferase activity in (C) EndoC-βH1 and (D) HepG2 cells (n=3 for each cell type). Results are presented as mean ± standard error. The risk allele had significantly increased enhancer activity over the protective allele in both forward and reverse orientations in both cell types.

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